Piperidinyl compounds

ABSTRACT

The present invention pertains to a new class of compounds which can be characterized as 1,4-disubstituted piperidinyl compounds useful as antiarrhythmics, analgesics, and serotonin 5HT 2  antagonists.

This is a divisional of application Ser. No. 07/797,643, filed 16 Dec.1991, now U.S. Pat. No. 5,166,211, which is a divisional application ofSer. No. 07/237,600, field 26 Aug. 1988 and now issued as U.S. Pat. No.5,093,341, which is a continuation-in-part of Ser. No. 07/134,406, filed17 Dec. 1987, now abandoned.

The present invention relates to novel 1,4-disubstituted piperidinylpharmaceutical compounds. Another aspect of the invention pertains tomethods for treating various disease states. A further aspect of thepresent invention relates to novel intermediate compounds useful insynthesizing said pharmaceutical compounds.

In accordance with the present invention, a new class of therapeuticagents have been discovered which can be represented by the formula:##STR1## wherein; Y is represented by H, CO(CH₂)_(n) CH₃ in which n isan integer from 0-3, or SO₂ (CH₂)_(n) CH₃ in which n is an integer from0-3; X is represented CO, CHOH, or C═N--O--A, wherein A is representedby hydrogen or a C₁₋₄ alkyl; R is either selected from the groupconsisting of halogens, lower alkyl groups, lower alkoxy groups, andhydrogen or R is a divalent substituent and is represented by a3,4-methylenedioxy or a 3,4-ethylenedioxy group; m is an integer from1-5; and the pharmaceutically acceptable acid addition salts thereof.

These compounds have a number of therapeutic indications. They are ClassIII antiarrhythmic agents, and non-narcotic analgesics. They are alsoserotonin 5HT₂ antagonists and thus are useful for treating a number ofdisease states.

As used in this application:

a) the term halogen refers to a fluorine, chlorine, or bromine atom;

b) the term lower alkyl group refers to a branched or straight chainedalkyl group containing from 1-4 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl and isobutyl;

c) the term lower alkoxy group refers to a straight or branched alkoxygroup containing from 1-4 carbon atoms, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy and isobutoxy;

d) the term carbonyl refers to a substituent having the followingstructure: ##STR2## e) the term hydroxymethyl group refers to thefollowing substituent, --CHOH--; f) the term oxime refers to asubstituent having the following structure:

    ═N--O--A

wherein A is represented by hydrogen or a C₁₋₄ alkyl;

g) the term 3,4-methylenedioxy or 3,4-ethylenedioxy refers to thefollowing substituent:

    --O--(CH.sub.2).sub.e --O--

wherein e equals 1 or 2.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by Formula I or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulfuric and phosphoric acid and acidmetal salts such as sodium monohydrogen orthophosphate and potassiumhydrogen sulfate. Illustrative organic acids which form suitable saltsinclude the mono-, di- and tri-carboxylic acids. Illustrative of suchacids are, for example, acetic, glycolic, lactic, pyruvic, malonic,succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid and sulfonic acidssuch as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Eitherthe mono- or di-acid salts can be formed, and such salts can exist ineither a hydrated or substantially anhydrous form. In general, the acidaddition salts of these compounds are soluble in water and varioushydrophilic organic solvents and which in comparison to their free baseforms, generally demonstrate higher melting points.

Some of the compounds of Formula I exist as optical isomers. Anyreference in this application to one of the compounds represented byFormula I is meant to encompass either a specific optical isomer or amixture of optical isomers. The specific optical isomers can beseparated and recovered by techniques known in the art.

In the compounds of Formula I in which R is represented by a monovalentsubstituent, there can be up to 3 such substituents occurring on theindicated phenyl ring. These

substituents can be located at any of positions 2-6 of the indicatedphenyl ring. These substituents can be the same or can differ from oneanother. When R is represented by a divalent substituent (i.e.3,4-methylene or ethylene dioxy), then the indicated phenyl ring shouldnot be substituted with any other substituents and the divalentsubstitution should appear at the 3 and 4 positions of the phenyl ring.The amino group which is represented by NHY, can be located at either ofpositions 2 or 4 of the indicated phenyl ring.

Representative examples of preferred compounds encompassed by Formula Iare those selected from the group consisting of:

1) N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]acetamide,

2)N-[4[hydroxy[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-acetamide,

3)N-[4-[hydroxy[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-methanesulfonamide,

4)N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]methanesulfonamide,

5)N-[4-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide,

6)N-[4-[[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide,

7)N-[4-[hydroxy-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]ethyl]phenyl]-methanesulfonamide,

8)N-[4-[hydroxy-[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl]phenyl]-methanesulfonamide,

9)N-[4-[[1-[2-(3,4-methylenedioxyphenyl)-ethyl]-4-piperidinyl]carbonyl]phenyl-methanesulfonamide,

10)N-[4-[hydroxy-[1-[2-(3,4-methylenedioxy-phenyl)ethyl]-4-piperidinyl]methyl]phenyl]-methanesulfonamide,

11)N-[4-[(methoxyimino)[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl-methanesulfonamide,

12) 4-aminophenyl[1-(2-phenylethyl)-4-piperidinyl]methanone,

13) and the pharmaceutically acceptable acid addition salts thereof.

The most preferred compounds of Formula I are those wherein; R isrepresented by at least one methoxy substituent, preferably 2; m is 2; nis 0; and the amino grouping is located at the 4-position in theindicated phenyl ring.

The compounds of Formula I can be synthesized by techniques known in theart. It is currently preferred that the compounds be synthesized in thefollowing novel manner.

If the desired compound is substituted with a carbonyl function at the4-position of the piperidinyl ring (i.e., in Formula I, X is CO), thenthe following synthesis is currently preferred.

A Friedel-Crafts acylation should be conducted with starting materialswhich can be described by the following formulae ##STR3## wherein Y isas defined in Formula I, and Z is selected from Br, Cl, I or F. Thecompound of Formula II is generally present as an acid addition salt.

This Friedel-Crafts acylation produces a novel intermediate of theFormula: ##STR4## wherein Y is as defined in Formula I.

The amino-substituted-phenyl compound (compound represented by FormulaIII) utilized as a starting material should correspond structurally toits analogous counterpart in the desired 4-substituted piperidinylintermediate since all of its substituents will be retained in theintermediate and ultimately the final product.

Likewise, the 4-halo-carbonyl-piperidine utilized as the startingmaterial (compound represented by Formula II) should correspondstructurally to its counterpart in the desired 4-substituted piperidinylintermediate since any substituents appearing on the piperidinyl ringwill be retained in the intermediate as well as the final product (withthe exception of the 4-halo substituent). Therefore, the piperidinylring of the 4-halo-carbonyl-piperidinyl compound should not besubstituted with any functional groups at the 1, 2, 3, 5, or 6 positionssince they would be retained in the final product.

For example if the desired 1,4-disubstituted piperidinyl compound isN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamide, thenits intermediate, N-[4-(4-piperidinyl-carbonyl)phenyl]acetamide can beproduced by reacting, a 4-halo-carbonyl-piperidine, with acetanilide.

It is currently preferred that approximately equimolar quantities of theamino-substituted phenyl compound and the 4-halo-carbonyl-piperidine bereacted together. A slight excess of either reactant will not bedeleterious to the reaction.

The reaction can be conducted with Friedel-Crafts catalysts known in theart, such as, for example, AlCl₃, ZnCl₂, AlBr₃, SnCl₄, etc. AlCl₃ iscurrently utilized.

The Friedel-Crafts catalyst is generally present in the reaction zone ina quantity of from 1-4 moles, and preferably from 3-4 moles, for everymole of 4-halocarbonyl-piperidine utilized in the reaction.

It is preferred that the Friedel-Crafts acylation be conducted for aperiod of time ranging from 0.2 to 24 hours.

It is also preferred that the Friedel-Crafts acylation be conducted at atemperature range of from 0°-100° C. The reaction can either beconducted neat or in an organic solvent.

The desired 4-substituted-piperidinyl intermediate can be recovered fromthe reaction zone by techniques known in the art. If the phenyl ring ofthe 4-substituted piperidinyl intermediate is substituted with either anamino grouping or an amide grouping (i.e., Y in Formula I is H orCO(CH₂)_(n) CH₃); then the intermediate can be recovered from thereaction zone by extraction with an organic solvent, after water hasbeen added to the reaction and the reaction zone has been renderedbasic. The resulting extract can be further purified or utilized as inthe next step of the synthesis. If the phenyl ring of the4-substituted-piperidinyl intermediate is substituted with a sulfonamidegrouping (i.e., Y in Formula I is SO₂ (CH₂)_(n) CH₃), then theintermediate can be recovered by adding water to the reaction zone andrecovering the resulting precipitated hydrohalide salt.

If desired, the 4-substituted piperidinyl intermediate can be purifiedby techniques known in the art.

The next step in the synthesis of the carbonyl containing1,4-disubstituted piperidinyl compounds is to react the 4-substitutedpiperidinyl intermediate (compound of Formula IV) obtained above with acompound of the formula: ##STR5## wherein R and m are as defined inFormula I and Z is selected from Br, Cl or I.

The aralkyl halide (compound of Formula V) utilized as a startingmaterial, preferably corresponds structurally to its counterpart in thedesired 1,4-disubstituted piperidinyl compound since all of itssubstituents with the exception of the halogen atom (Z) will be retainedin the final product.

For example, if the desired 1,4-disubstituted piperidinyl compound isN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamide, then1-halo-2-phenyl-ethane should be utilized as the aralkyl halidereactant.

It is currently preferred that the 4-substituted piperidinylintermediate (compound of Formula IV) and the aralkyl halide (compoundof Formula V) be present in the reaction zone in approximately equimolarquantities. A slight excess of either reactant will not be deleteriousto the reaction.

It is preferred that the reaction be conducted in the presence of abase. If the phenyl ring of the 4-substituted piperidinyl intermediateis substituted with a sulfonamide group (i.e., Y in Formula I is SO₂(CH₂)_(n) CH₃), then weak bases such as KHCO₃ are preferred. If thephenyl ring of the 4-substituted piperidinyl intermediate is substitutedwith either an amino grouping or an amide grouping (i.e., Y in Formula Iis H or CO(CH₃)_(n) CH₃), then stronger bases such as K₂ CO₃ or Na₂ CO₃may be utilized.

Preferably the base is present in the reaction zone in the molar ratioof from 1 to 2 moles of base per mole of 4-substituted piperidinylintermediate utilized.

The reaction is currently conducted in a solvent. Representativeexamples of suitable solvents include N,N-dimethylformamide, toluene andthe combination of toluene and water.

It is also preferred that the reaction be conducted in an inertatmosphere. Argon is currently utilized.

It is also preferred that the reaction be conducted at a temperaturerange of from 50-153° C., more preferably from 90°-95° C. It is alsopreferred that the reaction be conducted for a period of time rangingfrom 0.5 to 24 hours.

It is currently preferred that the solvent be removed from the reactionzone prior to the recovery of the desired 1,4-disubstituted piperidinylcompound. This can be accomplished by filtration or other suitabletechniques known in the art. The separated solvent which contains thedesired product is generally concentrated prior to further purification.

The desired 1,4-disubstituted piperidinyl compound can be recovered fromthe concentrate by extraction with an organic solvent after water hasbeen added to the concentrate.

The desired 1,4-disubstituted piperidinyl compound can be purified bytechniques conventionally used within the art. One suitable technique isto recrystallize the 1,4-disubstituted piperidinyl compounds from anappropriate solvent system. Representative examples of suitable solventsystems include 2-propanol/hexane, ethyl acetate/methanol, and the like.

Optionally, the 1,4-disubstituted piperidinyl compound can be subjectedto chromatography on a silica gel column prior to its beingrecrystallized.

If the desired 1,4-disubstituted piperidinyl compound is substitutedwith a hydroxymethyl group at the 4-position of the piperidinyl ring(i.e., X in Formula I is CHOH), then the following synthesis can beutilized.

A 1,4-disubstituted piperidinyl compound is prepared having a carbonylfunction at the 4-position of the piperidinyl ring (i.e., X in Formula Iis CO) that is otherwise structurally analogous to the desiredhydroxymethyl containing 1,4-disubstituted piperidinyl compound. Thiscan be accomplished in the manner disclosed above.

The carbonyl containing 1,4-disubstituted piperidinyl compound producedabove can then be subjected to a reduction reaction, thereby producingthe desired 1,4-disubstituted piperidinyl compound having ahydroxymethyl group located at the 4-position of the piperidinyl ring.

It is preferred that the carbonyl containing 1,4-disubstitutedpiperidinyl compound prepared correspond structurally to the desiredhydroxymethyl containing 1,4-disubstituted piperidinyl compound sinceall of its other substituents will be retained in the final product.

For example, if the desired compound isN-[4-[hydroxy[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-acetamide;then N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamideshould be prepared in the manner previously disclosed and then reducedwith an appropriate reducing agent thereby producing the desiredcompound.

A variety of reducing agents can be utilized to reduce the carbonylfunction into an alcohol. Representative examples of suitable reducingagents can be selected from the group consisting of sodium borohydride,lithium borohydride, aluminum isopropoxide, platinum metal catalyzedhydrogenations, etc.

It is preferred that the reducing agent be present in the reaction zonein a slight to moderate molar excess relative to the carbonyl containing1,4-disubstituted piperidinyl compound.

It is preferred that the reducing agent and the 4-carbonyl substitutedpiperidinyl compound be allowed to react for a period of time rangingfrom 0.1 to 16 hours and at a temperature range of from 0°-20° C.

It is also preferred that the reaction be conducted in a solvent.Representative examples of suitable solvents include methanol, ethanol,isopropanol and dioxane.

The desired hydroxymethyl containing 1,4-disubstituted piperidinylcompound can be recovered from the reaction zone in the mannerpreviously disclosed for the carbonyl containing 1,4-disubstitutedpiperidinyl compounds. Prior to further purification, it is preferredthat the resulting extract be subjected to chromatographic purificationtechnique such as flash chromatography.

If the desired hydroxymethyl containing 1,4-disubstituted piperidinylcompound is present as a free base, it can be purified by consecutiverecrystallizations from differing solvent systems. One suitablecombination is recrystallization from dichloro-methane/hexane, followedby isopropanol/water. An alternative is recrystallization from2-propanol/hexane followed by recrystallization from 2-propanol. If thedesired hydroxymethyl containing 1,4-disubstituted piperidinyl compoundis present as its acid addition salt, then it can be purified byrecrystallization from a solvent system such as methanol/ethyl acetateor methanol/isopropanol.

An alternative method of preparing the hydroxymethyl containing1,4-disubstituted piperidinyl compounds (i.e., where X in Formula I isCHOH), is the following synthetic procedure.

The first step in the synthesis is to prepare a 4-substitutedpiperidinyl intermediate as previously described in Formula IV. Thisintermediate should be structurally analogous to the 4-substitutedpiperidinyl residue appearing in the final product, with the exceptionof X being represented by a carbonyl group. The intermediate of FormulaIV is then subjected to a reduction reaction, thereby converting thecarbonyl substituent at the 4-position of the piperidinyl ring into ahydroxymethyl group. This reduction reaction can be conducted in ananalogous manner to the reduction previously described.

The reduced intermediate is then reacted with an aralkyl halide aspreviously described in Formula V, in a manner analogous to thatpreviously described, thereby producing the desired hydroxymethylcontaining 1,4-disubstituted piperidinyl compound.

For example, if the desired hydroxymethyl containing 1,4-disubstitutedpiperidinyl compound isN-[4-[hydroxy-[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-acetamide,then the first step is to prepare the intermediate of Formula IV,N-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide. This intermediate isthen reduced, thereby producingN-[4-(4-piperidinylhydroxymethyl)phenyl]-acetamide.

This reduced intermediate is then reacted with 1-halo-2-phenylethane,thereby producingN-[4-[hydroxy-[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-acetamide.

If the desired 1,4-disubstituted piperidinyl compound is substitutedwith an oxime group at the 4-position of the piperidinyl ring (i.e., Xin Formula I is C═N--O--A), then the following synthesis can beutilized.

A 1,4-disubstituted piperidinyl compound is prepared having a carbonylfunction at the 4-position of the piperidinyl ring (i.e., X in Formula Iis CO) that is otherwise structurally analogous to the desired oximecontaining 1,4-disubstituted piperidinyl compound. This can beaccomplished in the manner disclosed above.

The carbonyl containing 1,4-disubstituted piperidinyl compound can thencontacted with a hydroxylamine or an alkoxyamine, and via a nucleophilicaddition reaction, the desired piperidinyl compound having an oxime atthe 4-position of the piperidinyl ring will be produced.

The hydroxylamine or alkoxyamine which is utilized in the reaction canbe described by the following formula:

    NH.sub.2 --O--A

    Formula VI

wherein A is represented by hydrogen or a C₁₋₄ alkyl. In the amine whichis utilized, A should be analogous to that appearing in the desiredproduct. It also is preferred that the carbonyl containing1,4-disubstituted piperidinyl compound utilized in the nucleophilicaddition, correspond structurally to the desired oxime containing1,4-disubstituted piperidinyl compound since all of its othersubstituents will be retained in the final product.

For example if the desired oxime containing compound isN-[4-[(methoxyimino)[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl-methanesulfonamide,then the appropriate reactants areN-[4-[[1-(2-phenylethyl)-4-piperidinyl]-carbonyl]phenyl]-methanesulfonamideand methoxyamine.

The nucleophilic addition is accomplished according to techniques knownin the art. The carbonyl containing 1,4-disubstituted piperidinylcompound is contacted with the hydroxyl or alkoxy amine in the presenceof a weak organic base such as, for example, ammonium acetate. Thereactants are typically stirred together for a period of time rangingfrom 0.5 hours to 5 hours at a temperature range of from 0° to 120° C.It is preferred that the carbonyl containing 1,4-disubstitutedpiperidinyl compound and the hydroxyl or alkoxy amine be present in anapproximately equimolar quantity.

The desired oxime can be recovered from the reaction zone according totechniques known in the art. Typically the reaction zone will becontacted with a base such as sodium bicarbonate and the resultingaqueous layer is then extracted with an organic solvent such as ethylacetate. The desired oxime will be located in the resulting organiclayer. The acid addition salt of the oxime product can be formed asknown in the art, and is typically done prior to purification.

The oxime can also be purified according to techniques known in the art.For example if the product is present as the hydrochloride salt, it canbe purified by recrystallization from a methanol/2-butanone solventsystem. Other solvent systems suitable for use with other acid additionsalts of the oxime product will be readily apparent to those skilled inthe art.

Although those compounds of Formula I wherein Y is represented byhydrogen can be prepared utilizing the above described techniques, thesynthetic procedure described below is currently utilized for theirproduction.

Initially a 1,4-disubstituted piperidinyl compound as described byFormula I is prepared that is structurally analogous to the desiredcompound with the exception of Y be represented by CO(CH₂)_(n) CH₃ (i.e.an acetamide derivative). This can be done by the methods discussedabove.

This 1,4-disubstituted piperidinyl acetamide derivative is thensubjected to a hydrolysis reaction which serves to remove the acetylresidue and produces the desired compound wherein Y is H. Either anacidic or a basic hydrolysis can be utilized according to techniquesknown in the art. If X is represented by CHOH, then a basic hydrolysisshould be utilized.

For example, the acidic hydrolysis can be conducted by contacting theacetamide derivative with a mineral acid such as hydrochloric acid.Typically the mineral acid is present in a concentration of from 0.5 to12 moles per liter. The acetamide derivative is stirred in the acidicenvironment for a period of time ranging from 0.5 to 12 hours at atemperature range of from room temperature to 100° C.

The desired amino-substituted compound (i.e. Y is H) can be recoveredusing techniques known in the art. Typically the reaction medium isneutralized with a base when an acidic hydrolysis is utilized and thenextracted with an organic solvent such as chloroform.

The amino compound can also be purified using techniques known in theart. The organic layer obtained above is concentrated and dried. Theconcentrate is then filtered thru silica gel by eluting with acetone.The eluent is then concentrated until a solid is obtained. This solid isthen subjected to recrystallization in a solvent such as isopropanol.Other solvent systems will be readily apparent to those skilled in theart.

The compounds of Formula I can be administered by a variety of routes.They are effective if administered either orally or parenterally (i.e.,intravenously, intramuscularly, or subcutaneously).

Repetitive daily administration of the compounds may be desired and willvary with the conditions outlined below for the quantity of compoundutilized.

The compounds of the present invention are useful as cardiacantiarrhythmic agents. They can be administered to a patient sufferingfrom an arrhythmic episode in order to terminate the arrhythmic episodeand return the myocardium to a normal sinus rhythm or the compound canbe administered on a prophylactic basis in order to prevent theoccurrence of arrhythmic episodes.

The compounds of Formula I increase the duration of the action potentialof myocardial tissue producing an increase in the refractory period ofthat tissue. Thus, under the classification system of Vaughan Williamsthese compounds exhibit a Class III antiarrhythmic activity.

One method of demonstrating the antiarrhythmic activity of thesecompounds is the following test protocol. This protocol demonstrateswhat effect a compound has upon the action potential of isolated cardiactissue, such as a Purkinje fiber from a dog heart or a papillary musclefrom a guinea pig heart.

The heart of an anesthetized mongrel dog is surgically removed and thePurkinje fibers are dissected from either of the ventricles.Alternatively, papillary muscles are removed from the right cardiacventricle of a guinea pig. A Purkinje fiber or a papillary muscle isthen placed in a tissue bath which is continuously perfused withmodified Tyrode's solution¹.

mMol): NaCl 127.0, KCl 5.4, NaH₂ PO₄ 0.5, MgCl₂ 1.0, NaHCO₃ 23.8, CaCl₂1.8 and glucose 11.1. A gas mixture comprised of 95% O₂ and 5% CO₂ isbubbled through the solution while it is maintained within a pH range offrom 7.3-7.4.

The electrophysiology of the cardiac tissue is monitored by conventionalglass microelectrodes. One microelectrode is inserted into a cell in thecardiac muscle fiber and a ground electrode is positioned in the tissuebath. A conventional oscilloscope is utilized to visualize the actionpotential waveforms of the cardiac cell.

The cardiac muscle fiber is electrically stimulated at a frequency of 1Hz through a pair of platinum plates placed in the tissue bath. Thisstimulation is continued for approximately 1 hour in order to allow theelectrophysiological characteristics of the fiber to stabilize.

After approximately 1 hour, the fiber should be exhibiting a stableaction potential as demonstrated by the waveform displayed on theoscilloscope. At this point, representative control action potentialsare recorded and analyzed by a computer.

After establishing a control action potential, the test compound isintroduced into the Modified Tyrode's solution in a quantity such thatthe test compound is present within the tissue bath in a range of from10⁻⁸ to 10⁻⁵ moles/liter. After the effect of the test compound hasreached a steady state, the action potential is again recorded andanalyzed in the manner described above.

The compounds of the present invention having Class III antiarrhythmicproperties are useful for treating a variety of arrhythmic conditions ofthe heart. Representative examples of arrhythmic conditions which areamendable to treatment with the compounds of the present inventioninclude atrial tachycardia, atrial flutter, atrial fibrillation, supraventricular arrhythmias, and life threatening ventricular arrhythmiassuch as ventricular tachycardia, or ventricular fibrillation. Thesecompounds will also prevent recurrent episodes of the arrhythmiasmentioned above.

The quantity of compound needed to either terminate an arrhythmicepisode or prevent the occurrence of an arrhythmic episode (i.e., anantiarrhythmic quantity) will vary depending upon the route ofadministration, the patient, the severity of the patient's condition,the presence of other underlying disease states, and the particularcompound utilized. However as a general guideline, if the compound isbeing administered orally, then it is preferably administered within adosage range of from about 1.0 to about 400.0 mg/kg of patient bodyweight/day. Likewise, if the compound is being administered parenterallythen it is preferably administered within a dosage range of from about0.1 to about 120 mg/kg of patient body weight/day.

The patient's response to the compound can be monitored via an EKG orany other technique conventionally used in the art.

In addition to exhibiting an antiarrhythmic effect upon cardiac tissueat the doses described above, those compounds of Formula I wherein Y isrepresented by SO₂ (CH₂)_(n) CH₃ and X is represented by CO increase thecontractile force of cardiac tissue, (i.e. a cardiotonic effect). Thiscan be demonstrated in vitro by measuring the force of contraction inguinea pig papillary muscle.

Additionally the following known antiarrhythmic compounds increase thecontractile force of cardiac tissue within the dosage ranges describedabove: ##STR6## wherein p is an integer from 1-6 and Z is represented byNHSO₂ R¹, in which R¹ is Cl-6 alkyl. These compounds, their acidaddition salts, their optical isomers, as well as methods for theirproduction are known in the art. European Patent Application C235,752discloses this.

The compounds of Formula I are also non-narcotic analgesic agents. Thecompounds possess a level of potency sufficient to inhibit the sensationof the severe levels of pain that are commonly associated withconditions such as metastatic carcinoma, myocardial infarctions ortraumatic injuries.

Despite this high level of potency, the compounds are non-narcotic. Thismeans that they are devoid of the abuse potential that accompanies mostanalgesics.

One manner of demonstrating the analgesic utility of these compounds isto conduct the following test protocol. From 5 to 10 mice, should beadministered from 0.1 to 200 mg/kg of the compound either subcutaneouslyor intragastrically. Thirty minutes after the administration of the testcompound, the mice should be administered 0.4 ml of a 0.25% v/v solutionof acetic acid intraperitoneally.

Five minutes after the administration of the acetic acid, the miceshould be observed for signs of squirming and writhing which isindicative of pain.

A compound is considered to posses significant analgesic activity if themice which are administered said compound do not exhibit signs of painduring the test (i.e., squirming and writhing).

One manner of demonstrating the non-narcotic properties of thesecompounds is the following test protocol.

Three mice should be administered up to 800 mg/kg of the desiredcompound intraperitoneally. Thirty minutes later the mice should beplaced upon a hot plate which has been heated to a temperature of 55° C.

A compound is considered to be non-narcotic if the mice jump within thefirst 20 seconds of when they are initially placed upon the hot plate.

The quantity of compound required to produce this analgesic effect canvary widely depending upon the particular compounds utilized, theseverity of the patient's pain, the patient, the presence of otherunderlying disease states, the route of administration, and othertherapeutic agents which are being administered to the patient.Generally though, the compounds will produce an analgesic effect at adosage range of from about 0.5 mg/kg of patient body weight/day to about100 mg/kg of patient body weight/day if administered parenterally andfrom about 2 mg/kg of patient body weight/day to about 200 mg/kg ofpatient body weight/day if administered orally.

The compounds of Formula I are also serotonin 5HT₂ antagonists. Theability of the compounds to antagonize the effects of serotonin at the5HT₂ receptor can be demonstrated by the following protocol. In thistest, 5HT₂ receptors are exposed to both [³ H] spiroperidol, (asubstance known to have a non-specific affinity for the receptor) andthe test compound. The extent to which there is a decrease in binding ofthe [³ H] spiroperidol to the receptor is indicative of the affinity ofthe test compound for the 5HT₂ receptor.

Initially a suspension of 5HT₂ receptors should be prepared. Ratcerebrocortex tissue is homogenized in 30 volumes of ice cold 50 mM TrisCl buffer, pH 7.7, using a polytron (setting 7 for 10 seconds). Thehomogenate is centrifuged at 40,000×g for 10 minutes at 4° C. The pelletis resuspended in 30 volumes of ice-cold buffer using a Douncehomogenizer and centrifuged as before. The pellet is finally resuspendedin 30 volumes of buffer.

To incubation tubes are added 0.2 ml of the receptor suspension, 100 μlof a 0.6 nM solution of [³ H]spiroperidol, 100 μl of a solutioncontaining the test compound (present within a concentration range offrom 10⁻⁵ to 10⁻¹⁰ moles per liter) and enough buffer to produce a finalvolume of 1.0 ml. The tubes are then incubated at 37° C. for 15 minutes.The incubation is quickly terminated by adding 5 ml of ice-cold bufferto the test tubes and filtering the cooled suspension through a glassfiber filter under vacuum. The filters are washed twice with 5 ml ofcold buffer and then the filters are transferred scintillation vials.The filters are then analyzed via liquid scintillation spectrometry in8.0 ml of Omnifluor® containing 5% Protosol®.

The specific binding of [³ H] spiroperidol is measured as the excessover blanks made with 10 μM methiothepin. A test compound is consideredto have affinity for the 5HT₂ receptor if it displaces the [³ H]spiroperidol by a factor of at least 15%.

The ability of the compounds to antagonize the 5HT₂ receptor in vivo canbe demonstrated via the following test protocol.

At least 5 mice should be administered from 0.1 mg/kg to 200 mg/kg ofthe test compound. Approximately 30 minutes later, the animal isadministered 30 mg/kg of 5-methoxy-N,N-dimethyltryptamine (DMT)intraperitoneally. For six minutes immediately following theadministration of the DMT, the number of head twitches for each animalis counted. An absence of head twitches, is considered indicative of theability of the compound to antagonize the 5HT₂ receptor in vivo.

The dosage range at which these compounds exhibit their ability to blockthe effects of serotonin at the 5HT₂ receptor can vary depending uponthe particular compound being administered, the particular disease orcondition being treated and its severity, the patient, other underlyingdisease states the patient is suffering from, and other medications thatmay be concurrently administered to the patient. Generally though, thesecompounds will exhibit their serotonin 5HT₂ antagonist properties at adosage range of from about 0.2 mg/kg of patient body weight/day to about100 mg/kg of patient body weight/day.

Since the compounds are serotonin 5HT₂ antagonists, they are useful inthe treatment of a variety of disease states and conditions. Thecompounds of Formula I are useful in the treatment of anxiety, variantangina, anorexia nervosa, Raynaud's phenomenon, intermittentclaudication and coronary or peripheral vasospasms. These conditions anddiseases can be relieved by administering to a patient in need thereofof, a compound of Formula I in an amount sufficient to treat the diseaseor condition (i.e. an anxiolytic amount, anti-anginal amount,anti-anorexic amount, etc.). This quantity will be within the dosagerange at which the compounds exhibit their serotonin 5HT₂ antagonisticproperties.

The compounds are also useful in the treatment of thrombolyticillnesses. As known to those skilled in the art, a variety of conditionscan cause the initial aggregation of platelets. This initial aggregationof platelets produces a release of serotonin which induces the furtheraggregation of platelets. This further aggregation also stimulates thefurther release of serotonin. Thus a cycle is created wherein the clotcan expand until the blood vessel is occluded. It has been discoveredthat the compounds of Formula I prevent the further aggregation ofplatelets which is typically produced as the result of the release ofserotonin. Thus the compounds can be administered prophylactically in ananti-thrombotic quantity to a patient in need thereof to prevent theformation of thrombi capable of occluding blood vessels. Thisanti-thrombotic amount will be within the dosage range described abovewherein these compounds exhibit their serotonin 5HT₂ antagonist effects.Representative examples of patients who can benefit from such therapyinclude patients with atherosclerosis and coronary artery disease thatare experiencing transient ischemic attacks characterized by chest pains(angina pectoris) or other usual symptoms and patients who areundergoing thrombolysis with agents such as streptokinase or tissueplasminogen activator as well as patients undergoing coronary bypasssurgery.

The compounds of Formula I are also useful in the treatment offibromyalgia. As used in this application, fibromyalgia refers to achronic disease state wherein the patient suffers from numerous symptomssuch as for example, widespread generalized musculoskeletal pains,aching, fatigue, morning stiffness and a sleep disturbance which can becharacterized as an inadequacy of stage 4 sleep. Administration of thecompounds of Formula I in a anti-fibromyalgia amount relieves oralleviates the symptoms the patient is experiencing. Ananti-fibromyalgia amount will be within the dosage range described abovewherein these compounds exhibit their serotonin 5HT₂ antagonist effects.

The compounds of Formula I can also be used to treat the extrapyramidalsymptoms that often accompany the administration of neuroleptic agentssuch as haloperidol, chlorpromazine, etc. These extrapyramidal sideeffects (EPS) can manifest themselves in a variety of ways. Somepatients experience a parkinsonian-like syndrome, wherein theyexperience muscular rigidity and tremors. Others experience akathisia,which can be characterized as a compelling need for the patient to be inconstant movement. A few patients experience acute dystonic reactions,such as facial grimacing and torticollis.

The administration of a compound of Formula I to a patient in needthereof, in an anti-EPS amount will relieve or alleviate the symptomsthat the patient is experiencing. The amount of compound which producesthis anti-EPS effect is an amount within the dosage range at which thecompounds exhibit their serotonin 5HT₂ antagonistic effects.

As used in this application:

a) the terms anxiety, variant angina, anorexia nervosa, Raynaud'sphenomenon, and coronary vasospasms are used in the manner defined inthe 27th Edition of Dorland's Illustrated Medical Dictionary,

b) the term patient refers to a warm-blooded animal, such as for examplerats, mice, dogs, cats, guinea pigs, and primates such as humans.

c) the term arrhythmia refers to any variation from the normal rhythm ofthe heart beat. Also as used in this application, the termantiarrhythmic refers to a compound capable of either preventing oralleviating an arrhythmia,

d) the term analgesic refers to an agent which either relieves oralleviates the sensation of pain,

e) the term thrombolytic illness refers to the formation of thrombicapable of occluding blood vessels,

f) the term treat refers to either relieving or alleviating thepatient's disease or condition and,

g) the phrase "increasing the contractile force of cardiac tissue"refers the ability of the compounds to increase the strength of themuscular contractions occurring within the cardiac tissue.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, suspensions, or emulsions. Solid unit dosage forms can becapsules of the ordinary gelatin type containing, for example,surfactants, lubricants and inert fillers such as lactose, sucrose, andcornstarch or they can be sustained release preparations. In anotherembodiment, the compounds of Formula I can be tableted with conventionaltablet bases such as lactose, sucrose, and cornstarch in combinationwith binders, such as acacia, cornstarch, or gelatin, disintegratingagents such as potato starch or algenic acid, and a lubricant such asstearic acid or magnesium stearate. Liquid preparations are prepared bydissolving the active ingredient in an aqueous or non-aqueouspharmaceutically acceptable solvent which may also contain suspendingagents, sweetening agents, flavoring agents, and preservative agents asare known in the art.

For parenteral administration, the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers are water, saline, dextrose solutions, fructosesolutions, ethanol, or oils of animal, vegetative, or synthetic origin.The pharmaceutical carrier may also contain preservatives, buffers, etc.as are known in the art.

The following examples are presented in order to further illustrate thepresent invention. However, they should not be construed as limiting thescope of the invention in any manner.

EXAMPLE 1

The purpose of this example is to demonstrate a manner of preparing anintermediate of Formula IV,N-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide.

33.9 g of N-phenyl-acetamide (251 mmol) was admixed with 45 g of AlCl₃(338 mmol). This mixture was placed in a 5 liter round bottom flask,mechanically stirred and heated with steam until a dark viscous solutionwas obtained.

To this solution was added consecutively 46.0 g of 4-chloro-carbonylpiperidine hydrochloride (250 mmol) and 90 g of AlCl₃ (675 mmol). Thisproduced a dark red paste.

The paste was heated with steam for 15 minutes and then 100 ml of1,1,2,2-tetrachloroethane was added which produced a translucent redsolution. This solution was then heated for an additional 10 minutes.

The steam bath was then removed and the reaction was quenched by theslow addition of 2 kg of cracked ice. The solution was made stronglybasic with a 50% NaOH solution. This cold aqueous solution was thenwashed twice with toluene, and extracted twice with chloroform. Thecombined chloroform extracts were dried over MgSO₄ and evaporated toyield a yellow solid. The solid was washed in refluxing ethyl acetate at76° C. and filtered to affordN-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide (20 g) as a light yellowsolid.

A portion of this product was then converted into a hydrochloride acidaddition salt in the following manner.

To 30 ml of stirred methanol under argon at 0° C. was added acetylchloride (0.95 ml, 0.86 g, 13.4 mmol) dropwise with a syringe. Thissolution was then added dropwise to 3.0 g of theN-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide (12.2 mmol, preparedabove) which had been dissolved in 50 ml of methanol.

This solution was then heated to reflux and diluted with 100 ml ofrefluxing ethanol. This admixture was then concentrated to a volume of75 ml.

The solution was cooled to room temperature which caused theprecipitation of the intermediateN-[4-(4-piperidinyl-carbonyl)phenyl]-acetamide as the monohydrochloridesalt. 1.7 g of N-[4-(4-piperidinyl-carbonyl) phenyl]-acetamidemonohydrochloride (6.0 mmol) was obtained which had a melting point of285° C.

EXAMPLE 2

The purpose of this example is to demonstrate a manner of preparing the1,4-disubstituted piperidinyl compound,N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]acetamide.

13.0 g of N-[4-(4-piperidinyl-carbonyl)phenyl]acetamide (52.8 mmol) wasprepared in the manner disclosed in Example 1 and admixed with 9.62 g of1-bromo-2-phenylethane (52.0 mmol), 13.0 g of K₂ CO₃ (94.1 mmol) and 150ml of N,N-dimethylformamide. This admixture was stirred under an argonatmosphere at 95° C. for 16 hours.

The mixture was then cooled to 22° C. and the N,N-dimethylformamide wasremoved from the salts by decantation. The decantedN,N-dimethylformamide was concentrated at reduced pressure on a rotaryevaporator until a tan solid was obtained.

This tan solid was partitioned between water and dichloromethane. Thelayers were separated and the organic layer was saved for furtherrecovery. The aqueous layer was extracted with dichloromethane and theresulting organic layer was saved for further purification.

The two previously saved organic layers were then dried over MgSO₄ andevaporated on a rotary evaporator until a yellow oil was obtained.

The yellow oil was then dissolved in 150 ml of 2-propanol which had beenheated to reflux. This solution was then diluted with refluxing hexaneuntil a total volume of 500 ml had been obtained.

The solution was then cooled to approximately 22° C. and filtered. 14.3g of N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamide(40.8 mmol) was obtained.

A portion of this product was then converted into a hydrochloride acidaddition salt in the following manner.

To 30 ml of stirred methanol which had been cooled to 0° C. was addedacetyl chloride (0.9 ml, 0.99 g, 12.6 mmol) dropwise via a syringe underan argon atmosphere.

4.0 g of theN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamide (8.3mmol, prepared above) was dissolved in 600 ml of methanol. To thissolution was added dropwise the solution of HCl inmethylacetate/methanol described above.

After completion of the addition, the solution was stirred for 5 minutesand then concentrated by a rotary evaporator at a reduced pressure to afinal volume of 80 ml.

Ethyl acetate was then slowly added to the solution which caused theprecipitation of crudeN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamidemonohydrochloride.

The precipitate was then dissolved in refluxing methanol and admixedwith activated charcoal, and filtered. The filtrate was admixed with2-propanol which had been heated to a temperature of 82° C. and thedesired compound crystallized after cooling.

The product was filtered and dried to give 2.6 g ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]acetamidehydrochloride, m.p. 257° C.

EXAMPLE 3

The purpose of this example is to demonstrate a manner of preparing anintermediate of Formula IV,N-[4-(4-piperidinyl-carbonyl)phenyl]-methanesulfonamidemonohydrochloride.

42.8 g of N-phenyl methanesulfonamide (250 mmol) was admixed with 45 gof AlCl₃ (338 mmol) in a 5 liter round bottom flask and heated withsteam while being mechanically stirred. A dark viscous solution wasobtained.

This solution was mixed with 46.0 g of 4-chlorocarbonyl piperidinehydrochloride (250 mmol) and 90.0 g of AlCl₃ (675 mmol) which produced adark brown sludge.

1,1,2,2-Tetrachloroethane (100 ml) was added and the admixture washeated for an additional 15 minutes.

Heating was discontinued and the reaction was quenched by the additionof 4 kg of cracked ice. A gray precipitate was obtained.

The precipitate was recovered by filtration. The resulting solid waswashed consecutively with water and ethyl ether and then air dried.

The resulting solid was dissolved in hot water, admixed with activatedcharcoal and filtered. The solution was then cooled to approximately 22°C. at which point the desired product precipitated from solution.

The solid material was filtered and dried to give 29.6 g ofN-[4-(4-piperidinyl-carbonyl)phenyl]-methanesulfonamidemonohydrochloride (92.8 mmol) which had a melting point of 303°-305° C.

EXAMPLE 4

The purpose of this example is to demonstrate a manner for preparing the1,4-disubstituted piperidinyl compound,N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide.

11.1 g of N-[4-(4-piperidinyl-carbonyl)phenyl]-methanesulfonamidemonohydrochloride (34.8 mmol) prepared as in the manner disclosed inExample 3 was admixed with 6.5 g of 1-bromo-2-phenylethane (35.2 mmol)and 7.1 g of KHCO₃ (71.0 mmol) and 100 ml of N,N-dimethylformamide.

This admixture stirred under an argon atmosphere for 16 hours at atemperature of 90° C.

This admixture was then cooled to approximately 22° C. TheN,N-dimethylformamide was decanted off and was concentrated on a rotaryevaporator, thereby producing a tan solid.

This solid was partitioned between water and dichloromethane. The layerswere separated and the organic layer was saved for further purification.The aqueous layer was extracted with dichloromethane and the organiclayer was separated and saved for further purification.

The organic layers were combined, dried over MgSO₄ and then concentratedat reduced pressure on a rotary evaporator which produced a yellow oil.

The oil was then dissolved in acetone and filtered through a pad ofsilica gel. The resulting filtrate was then concentrated to an oil whichwas diluted with 2-butanone which had been heated to reflux.

The butanone solution was cooled to approximately 22° C. and filteredthereby producing yellow crystals which were air dried.

3.2 g ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide(8.3 mmol) was obtained.

Methanol (1.5 ml) was admixed with 25 ml of ethyl acetate and cooled to0° C. To this solution was added acetyl chloride (0.73 ml, 0.66 g, 8.5mmol) dropwise with a syringe under an argon atmosphere.

After 5 minutes, this solution was added to the 3.2 g ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]methanesulfonamide(8.3 mmol, prepared above) which had been dissolved in 200 ml of stirredethyl acetate.

This addition caused the precipitation of a white solid. The solid wasrecovered from the solution by filtration and air dried.

The solid was then dissolved in approximately 100 ml of refluxingmethanol, admixed with activated charcoal and filtered. The filtrate wasadmixed with 2-propanol and the desired compound was obtained byrecrystallization.

2.0 g ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-methanesulfonamidemonohydrochloride (4.7 mmol) was obtained which had a melting point of117.5°-118.5° C.

EXAMPLE 5

The purpose of this example is to demonstrate a manner of preparing thehydroxymethyl containing 1,4-disubstituted piperidinyl compound,N-[4-[hydroxy-[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-acetamide.

5.0 g ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-acetamide(prepared in the manner described in Example 2) was admixed with 250 mlof methanol, and then was cooled to 0° C. The solution was stirred while0.54 g of sodium borohydride (14.3 mmol) was added. The solution wasstirred for an additional hour.

An additional 0.5 g of sodium borohydride was added and the solution wasstirred overnight.

The next morning 100 ml of water was added to the solution. The solutionwas then concentrated at reduced pressure to approximately 1/2 volume.The concentrate was subjected to two extractions with dichloromethaneand the resulting organic layers were combined for further purification.

The organic layers were dried over MgSO₄ and filtered through a pad ofsilica gel utilizing an acetone eluent. The filtrate was then evaporatedat reduced pressure by a rotary evaporator, thereby producing a whitesolid.

The desired hydroxymethyl containing 1,4-disubstituted piperidinylcompound was obtained from the white solid by: a) recrystallization froma dichloromethane/hexane solvent system, and b) subsequentrecrystallization from an isopropanol/water solvent system. Theresulting white needles were dried at 79° C. and 0.5 mm Hg for 40 hours.

1.44 g ofN-[4-[hydroxy[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-acetamide(3.7 mmol) was obtained which had a melting point of 173°-174° C.

EXAMPLE 6

The purpose of this example is to demonstrate a manner of preparing thehydroxymethyl containing 1,4-disubstituted piperidinyl compound,N-[4-[hydroxy-[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-methanesulfonamide.

4.85 g ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-methanesulfonamidehydrochloride (11.5 mmol) which had been prepared in the mannerdisclosed in Example 4 was admixed with 500 ml of methanol and thencooled to 0° C. The solution was stirred and 3.2 g of sodium borohydride(84.6 mmol) was added to this solution in 3 portions over the next 3hours.

The solution was stirred overnight and concentrated at reduced pressureon a roto evaporator. The resulting white solid was partitioned betweenwater and chloroform. The organic layer was saved for furtherpurification. The aqueous layer was extracted with chloroform and theresulting organic layer was saved.

The organic layers were combined, dried over MgSO₄, and and thenevaporated at reduced pressure by a roto evaporator to give a whitesolid.

The desired hydroxymethyl containing 1,4-disubstituted piperidinylcompound was purified from the white solid by: a) recrystallization froma 2-propanol/hexane solvent system and, b) subsequent recrystallizationfrom 2-propanol.

This produced 1.9 g ofN-[4-[hydroxy-[-1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]-methanesulfonamide(4.9 mmol) which had a melting point of 164.5°-165.5° C.

EXAMPLE 7

The purpose of this example is to demonstrate a manner of preparingN-[4-[[1-2-(4-methoxyphenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide.

The intermediate N-[4-(4-piperidinyl-carbonyl)phenyl]-methanesulfonamidewas prepared in a manner analogous to Example 1.

A slurry of N-[4-(4-piperidinyl-carbonyl)phenyl]methanesulfonamidemonohydrochloride (18.4 g, 57.6 mmol),1-bromo-2-(4-methoxyphenyl)-ethane (12.4 g, 57.6 mmol), and potassiumbicarbonate (11.5 g, 115 mmol) in N,N-dimethylformamide (180 ml) wasstirred under argon at 100° C. for 16 hours. After cooling to roomtemperature, the dimethylformamide was decanted away from the salts, andthe solution was concentrated at reduced pressure to a dark oil. Theoil, along with the salts, was partitioned between water and ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate. The combined organic layers were washed twice withwater, brine, dried over MgSO₄, and evaporated to give an off-whitesolid (20.6 g). The solid was dissolved in ethyl acetate (600 ml) andtreated with HCl in ethyl acetate to afford a white solid (20.2 g). Thesolid was recrystallized from methanol/isopropanol to yieldN-[4-[[1-2-(4-methoxyphenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamidemonohydrochloride (16.5 g, 36.3 mmol) as white, shiny flakes; m.p.246°-247° C.

EXAMPLE 8

The purpose of this example is to demonstrate a method for thepreparation ofN-[4-[[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide.

The intermediate N-[4-(4-piperidinyl-carbonyl)phenyl]methanesulfonamidemonohydrochloride was prepared in a manner analogous to Example 1.

A slurry of N-[4-(4-piperidinyl-carbonyl)phenyl]-methanesulfonamidemonohydrochloride (12.3 g, 38.4 mmol), 1-bromo-2-(4-fluorophenyl)-ethane(7.8 g, 38.4 mmol), and potassium bicarbonate (7.7 g, 77.0 mmol) inN,N-dimethylformamide was stirred under argon at 100° C. for 16 hours.After cooling to room temperature, the dimethylformamide was decantedaway from the salts, and the solution was concentrated to an oil. Theoil, along with the salts, was partitioned between water and chloroform.The layers were separated and the aqueous layer was extracted withchloroform. The combined organic layers were dried over MgSO₄ andevaporated and evaporated to give an oil (18 g). The oil was dividedinto two, 9 g portions, and consecutively chromatographed on silica gel,eluding with 1:4 acetone:ethyl acetate, to give a solid (11.0 g). Thesolid was dissolved in methanol (200 ml) and treated with HCl inmethanol. The entire solution was evaporated and the resulting off-whitesolid was recrystallized from methanol/isopropanol to afford N-[4-[[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide(5.94 g) as white crystals; m.p. 230°-230.5° C.

EXAMPLE 9

The purpose of this example is to demonstrate a method for thepreparation ofN-[4-[hydroxy-[1-[2-(4-methoxy-phenyl)ethyl]-4-piperidinyl]methyl]phenyl]-methane-sulfonamide.

To a stirred solution ofN-[4-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methane-sulfonamide(5.50 g, 13.2 mmol which had been prepared in the manner described inExample 7), in methanol (450 ml), at 0° C., was added sodium borohydride(600 mg, 15.9 mmol) in one portion. Two additional 600 mg portions ofsodium borohydride were added consecutively at 1.5 hour intervals andthe solution was allowed to stir overnight. The reaction mixture wasevaporated to a white solid and mixed into 200 ml of dilute aqueous HCl.The aqueous solution was neutralized with sodium bicarbonate andextracted three times with chloroform. The combined organic layers weredried over MgSO₄, and evaporated to give an off-white solid (5.2 g). Thesolid was chromatographed on silica gel, eluding with acetone, to giveN-[4-[hydroxy-[1-[2-(4-methoxyphenyl) ethyl]-4-piperidinyl]methyl]phenyl]-methanesulfonamide (15.1 g, 12.2 mmol) as an off-whitesolid; m.p. 40°-48° C.

EXAMPLE 10

The purpose of this example is to demonstrate a method for thepreparation ofN-[4-[hydroxy-[1-[2-(4-fluoro-phenyl)ethyl]-4-piperidinyl]methyl]phenyl]-methane-sulfonamide.

To a stirred solution of N-[4-[[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamide (9.50 g, 23.5mmol which had been prepared in the manner disclosed in Example 8), inmethanol (500 ml), at 0° C., was added sodium borohydride (1 g, 26.5mmol) in one portion. Three more 1-gram portions of sodium borohydridewere added consecutively at 1-hour intervals and the solution wasallowed to stir overnight. The solution was evaporated to dryness andthe solid was stirred into dilute aqueous HCl (200 ml). The aqueoussolution was neutralized with sodium bicarbonate and extracted threetimes with chloroform. The combined organic layers were dried overMgSO₄, and evaporated to give a white solid (8.2 g). The solid wasrecrystallized from chloroform to afford white flakes (5.7 g). The whiteflakes were found to beN-[4-[hydroxy-[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl]phenyl]methanesulfonamidecontaining one equivalent of chloroform.

EXAMPLE 11

The purpose of this example is to demonstrate a manner, of preparingN-[4-[[1-[2-(3,4-methylenedioxyphenyl)-ethyl]-4-piperidinyl]carbonyl]phenyl]-methanesulfonamidemonohydrochloride. A slurry ofN-[4-(4-piperidinylcarbonyl)phenyl]-methanesulfonamide monohydrochloride(20.9 g, 65.6 mmol), 1-bromo-2-(3,4-methylenedioxyphenyl)-ethane (15.0g, 65.5 mmol), potassium bicarbonate (13.1 g, 131 mmol) andN,N-dimethyl-formamide (200 ml) was stirred under argon at 95° C. for 16hours. After cooling to room temperature, the solution was filtered andthe filtrate concentrated to a yellow oil. The oil was partitionedbetween water and ethyl acetate, the layers separated, and the aqueouslayer extracted with ethyl acetate. The combined organic layers werewashed with water, brine, dried (MgSO₄), concentrated to ca. 100 ml, andchromatographed on silica(100×165 mm) eluting with ethylacetate. Theappropriate fractions were combined and treated with hydrogen chlorideto afford the product (22.0 g, 47.1 mmol,) as a white solid. The solidwas refluxed in methanol and filtered to give the desired product (15.0g, 28.0 mmol); m.p. 236°-237° C.

EXAMPLE 12

The purpose of this example is to demonstrate a manner of preparingN-[4-[hydroxy-[1-[2-(3,4-methylenedioxyphenyl)ethyl]-4-piperidinyl]methyl]phenyl]-methanesulfonamide.

A slurry ofN-[4-[[1-[2-(3,4-methylenedioxyphenyl)ethyl-4-piperidinyl]carbonyl]phenyl]-methanesulfonamidemonohydrochloride prepared as in Example 11 (10.2 g, 21.8 mmol) andmethanol (400 ml) was treated with potassium borohydride (9.6, 178 mmol)in eight portions over a period of three days. The solution wasacidified with 10% hydrochloric acid, and the pH adjusted to eight withsaturated sodium bicarbonate. This aqueous solution was concentrated andthen extracted twice with ethylacetate. The combined organic layers weredried (MgSO₄), and evaporated to give a white solid (7.9 g). The solidwas chromatographed on silica (75×160 mm), eluting with acetone toafford the desired product (4.8 g, 11.1 mmol) as a white solid; m.p.72°-73° C.

EXAMPLE 13

The purpose of this example is to demonstrate a manner of preparingN-[4-[(methoxyimino)[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl-methanesulfonamide.

A solution ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]-methanesulfonamidemonohydrochloride prepared as in Example 4 (6.0 g, 14.2 mmol),methoxyamine monohydrochloride (3.0 g, 35.9 mmol), and ammoniumacetate(120 g, 156 mmol), was prepared in ethanol (90 ml) and water (30 ml) andrefluxed for 16 hours. The solution was cooled, concentrated, andtreated with aqueous sodium bicarbonate. This basic, aqueous layer wasextracted twice with ethyl acetate. The combined organic layers weredried (MgSO₄), filtered, and treated with hydrogen chloride to afford awhite solid (6 g). The solid was recrystallized from methanol/2-butanoneto yield the desired product (2.3 g, 10.8 mmol) as a white, crystallinematerial; m.p. 234.0°-234.5° C.

EXAMPLE 14

The purpose of this Example is to demonstrate the production of a1,4-disubstituted piperidinyl compound according to Formula I wherein Yis represented by H.

A solution ofN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl/acetamide (32.1g, 91.6 mmol), conc hydrochloric acid (300 ml), and ethanol (300 ml) wasprepared and refluxed for six hours. The cooled solution was treatedwith 50% NaOH (200 g), concentrated, and extracted twice withchloroform. The combined organic layers were dried (MgSO₄),concentrated, and filtered through a pad of silica gel (eluting withacetone). The eluent was concentrated and the resulting solid wasrecrystallized from isopropanol to give4-aminophenyl[1-(2-phenylethyl)-4-piperidinyl]methanone as tan spears(20.3 g, 72%): m.p. 171°-172° C.

EXAMPLE 15

This example demonstrates a less preferred technique for the productionof a piperidinyl compound according to formula I wherein Y isrepresented by H and X is represented by CHOH. The carbonyl group of thestarting material was reduced and the acetamide group was allowed tohydrolyze in situ, rather than conducting the reduction and hydrolysisas distinct steps.

To N-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]acetamide(40.0 g, 114 mmol) in methanol (900 ml) was added potassium borohydride(16 g, 300 mmol), in small portions, over a 6 hour period. Water (200ml) was added and the solution was stirred for 20 hours. The solutionwas concentrated and partitioned between water and dichloromethane. Thelayers were separated, the organic layer dried (MgSO₄), filtered, andconcentrated. The resulting material was chromatographed on silica gel,eluting with 10% methanol in chloroform. The appropriate fractions werecombined, evaporated, and the resulting solid recrystallized from2-propranol/water to affordα-(4-aminophenyl)-1-(2-phenylethyl)-4-piperidine methanol as a whitesolid (7.5 g, 21%): m.p. 129°-130° C.

What is claimed is:
 1. A 1,4-disubstituted piperidinyl compound havingthe formula: ##STR7## wherein; Y is CO(CH₂)_(n) CH₃ in which n is aninteger from 0-3; X is selected from the group consisting of C═O andCHOH; R is selected from the group consisting of hydrogen, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, 3,4-methylenedioxy and 3,4-ethylenedioxy; m is aninteger from 1-5 and the pharmaceutically acceptable acid addition saltsthereof.
 2. A compound of claim 1 which isN-[4-[[1-(2-phenylethyl)-4-piperidinyl]carbonyl]phenyl]acetamide and thepharmaceutically acceptable salts thereof.
 3. A compound of claim 1which isN-[4-[hydroxy-[1-(2-phenylethyl)-4-piperidinyl]methyl]phenyl]acetamideand the pharmaceutically acceptable salts thereof.